Evaluating Clustetin-siRNA loaded lipid-based nanoparttcles for treating Parkinson's disease
Progetto 4.1 Abstract Parkinson’s disease (PD) is a neurodegenerative disorder characterized by
the selective loss of dopaminergic neurons and the presence of protein inclusions, mainly composed of o-synuclein (o-syn), in surviving neurons and in glia. The progressive neuropathological dama8e seen in PD is thought to be related to the neuron-to-neuron propagation of o-syn aggregated species. Indeed, n-syn has emerged as the major PD-therapeutic target and
several approaches are aimed at inhibiting its aggregation and/or targeting processes that may lead to n-syn propagation between neurons. In this regard, modulation of molecular chaperones is one of the most promising approaches to counteract o-syn burden. Of interest, Clusterin (Clu) is a well- known extracellular ehaperone highly expressed in the brain, which exhibits even intracellular activity under stress conditions. Thus, thanks to its different localization/function, Clu might counteract both the toxic effect of o-syn aggregation inside the cell and the ability of a-syn aggregates to spread between neurons. We collected several results (published and unpublished) showing that Clu is implicated in the o-syn pathology at both neuronal and astrocytic level with an enigmatic mechanism still to be elucidated. Specifically, we found that extracellular Clu limits the uptake of o-syn fibrils by murine and human astrocytes, indicating that Clu may influence the spreading of o-syn species between neurons and thus its presence could be detrimental for PD. While, at neuronal side, we observed that Clu inhibits the aggregation of o-syn, suggesting that in neuronal cells its presence is protective. Of relevant interest, in post-mortem brains of PD patients, we found increased (i) amount of Clu, (ii) CIu-positive neurons and (iii) an “aggregated” state of Clu compared to control subjects. Collectively, these findings suggest a crucial role of Clu in PD pathology that is worth to further investigation in an in vivo context. Therefore, in this project we propose to investigate the implication of Clu in PD in vivo; specifically, we will explore
whether Clu down-modulation, by using Clu- small interfering RNA
(siRNA) loaded solid lipid-based nanoparticles (SLNs), could be a potential therapeutic strategy for treating PD. Results from this project will deliver a better understanding of the role of Clu in PD pathogenesis and allow us to identify Clu as a new PD-therapeutic target. Clu represents an attractive target, because with its double function might provide a unique opportunity to inhibit intracellular o-syn aggregation and clear extracellular o-syn, thus limiting the spread of PD. This project will represent the starting point to develop a translational research approach aimed to pharmacologically
modulate Clu for treating PD.